A review of the effects of artemether-lumefantrine on gametocyte carriage and disease transmission.

Makanga M - Malar. J. (2014)

Bottom Line:
For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical.Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes.Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage.

ABSTRACTWhile significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.

Figure 1: Life cycle of Plasmodium falciparum. Artemisinin acts at an early stage of the erythrocytic stage of the parasite’s life cycle and is also effective against the gametocyte stage, thereby potentially interrupting transmission of malaria [8]. (Sourced from Hommel M 2008, with permission [8]).

Mentions:
The Plasmodium life cycle and targets of ACT and older generation, non-ACT anti-malarials are illustrated in Figure 1[8]. Key to the transmission of malaria is the differentiation within red blood cells of a small number of haploid asexual parasites into male and female gametocytes. Following their ingestion by the mosquito, these male and female gametes fuse to form a zygote and then an oocyst. Multiple rounds of DNA replication result in the production of thousands of sporozoites that are transmitted to humans via the mosquito’s salivary glands, and the cycle begins again. Gametocytes are also integral to the transmission and propagation of disease resistance; compared with drug-sensitive infections, resistant infections are associated with increased rates of recrudescence and slower initial treatment responses, both of which increase gametocyte densities. This suggests that increased gametocyte carriage in infections caused by resistant parasites results in a transmission advantage that ultimately helps to drive the spread of resistance [9,10].

Figure 1: Life cycle of Plasmodium falciparum. Artemisinin acts at an early stage of the erythrocytic stage of the parasite’s life cycle and is also effective against the gametocyte stage, thereby potentially interrupting transmission of malaria [8]. (Sourced from Hommel M 2008, with permission [8]).

Mentions:
The Plasmodium life cycle and targets of ACT and older generation, non-ACT anti-malarials are illustrated in Figure 1[8]. Key to the transmission of malaria is the differentiation within red blood cells of a small number of haploid asexual parasites into male and female gametocytes. Following their ingestion by the mosquito, these male and female gametes fuse to form a zygote and then an oocyst. Multiple rounds of DNA replication result in the production of thousands of sporozoites that are transmitted to humans via the mosquito’s salivary glands, and the cycle begins again. Gametocytes are also integral to the transmission and propagation of disease resistance; compared with drug-sensitive infections, resistant infections are associated with increased rates of recrudescence and slower initial treatment responses, both of which increase gametocyte densities. This suggests that increased gametocyte carriage in infections caused by resistant parasites results in a transmission advantage that ultimately helps to drive the spread of resistance [9,10].

Bottom Line:
For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical.Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes.Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage.

ABSTRACTWhile significant advances have been made in the prevention and treatment of malaria in recent years, these successes continue to fall short of the World Health Organization (WHO) goals for malaria control and elimination. For elimination strategies to be effective, limited disease transmission, achieved through rapid reduction in the infectious parasite reservoir and decreased gametocyte carriage, will be critical. Artemisinin-based combination therapy (ACT) forms the cornerstone of WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria, and in combination with other effective interventions will undoubtedly play a vital role in elimination programmes. The gametocytocidal properties of artemisinins are a bonus attribute; there is epidemiological evidence of reductions in malaria incidence and transmission in African regions since the introduction of these agents. Many studies and analyses have specifically investigated the effects of the ACT, artemether-lumefantrine (AL) on gametocyte carriage. In this systematic review of 62 articles published between 1998 and January 2014, the effects of AL on gametocyte carriage and malaria transmission are compared with other artemisinin-based anti-malarials and non-ACT. The impact of AL treatment of asymptomatic carriers on population gametocyte carriage, and the potential future role of AL in malaria elimination initiatives are also considered. Despite the inherent difficulties in comparing data from a range of different studies that also utilized different diagnostic approaches to assess baseline gametocyte counts, the gametocytocidal effect of AL was proportionately consistent across the studies reviewed, suggesting that AL will continue to play a vital role in the treatment of malaria and contribute to clearing the path towards malaria elimination. However, the specific place of AL is the subject of much ongoing research and will undoubtedly be dependent on different demographic and geographical scenarios. Utilizing ACT, such as AL, within malaria elimination strategies is also associated with a number of other challenges, such as balancing potential increased use of ACT (e g, treatment of asymptomatic carriers and home-based treatment) with rational use and avoidance of drug resistance development.